An overlooked gold mine

The underground, or the dark side of science if you will, is a much overlooked gold mine of top-notch information. We traditional medicinal, synthetic and process chemists in industry and academia have a lot to learn from our underground “colleagues.” A great deal of research and development in practically all aspects of organic synthesis and in vivo pharmacology is currently ongoing on a massive and global scale, right under our noses (Figure 1), whether we like it or not.

Figure 1. A synthesis performed in a very non-GMP certified laboratory

Due to the illegal nature of these endeavors however, the vast majority of the information produced in these laboratories and “clinics” (read: the street) will never surface in fancy conference rooms, the primary literature, patent applications or quarterly reports (you could not possibly have missed Breaking Bad, could you?). SciFinder, MARPAT, Reaxys, Google Scholar and PubMed only take us so far.

I do not condone breaking laws or regulations, and for the record I think the whole “research chemical” industry stinks more than ethanethiol and pyrrolidine together. Nevertheless, let us take an unbiased look at what we have here, and what possibilities there are for us to actually learn new things that might be of benefit to our own purposes and future achievements.

To start off, I would like to highlight two or three objectives that traditional and underground researchers very much have in common.

1. Optimal conditions

One such thing is the never-ending mismatch between the supply and demand of desired starting materials. While a graduate student may curse his supervisor for not allowing him or her to buy the latest and most awesome ruthenium catalyst (the supervisor tells the student to go synthesize it himself), the situation is pretty much identical for the underground chemist. The latter may for example at one point need a barrel of benzaldehyde, but since it is listed as a controlled precursor (spot on), it may be difficult to order it off the shelf without raising too much unwanted attention. The graduate student has to come up with a way of making his desired catalyst himself starting from relatively cheap reagents, and the underground chemist has to develop methods for turning some everyday compound into benzaldehyde. If the graduate student is fortunate enough to develop a new superior method, he then likely proceeds to publish, and in due time the whole community gains access to the recipe. On the other hand, when the underground chemist finds a new and fantastic method to oxidize toluene to selectively give benzaldehyde in great yield, the method stays within the underground community. Even though – which is my whole point here – everyone would love having access to the details of the process. Even if we are not interested in producing illegal narcotics, we could use the information in a number of other scenarios where we need to oxidize an aryl methyl group to the corresponding aldehyde.

2. Cost of manufacture

Another aspect, perhaps more applicable to the scale-up or process chemist, is the cost of goods, cost of manufacture or whatever you prefer to call the dreaded balance sheet. While the typical industrial medicinal chemist never has to take the price of the starting materials into account, since he or she only makes the few milligrams or less needed for the primary assays, the people responsible for scaling up the syntheses of the most promising lead compounds are very interested to know the exact overall cost. I guess the same goes for the underground chemist. What good is a quantitative yield if the starting materials and the cost of operations are higher than you could possibly get in return? I suspect many underground operators are highly skilled in the art of calculating the precise cost of manufacture for a given process.

3. Serendipity

We all know the story of sildenafil (Viagra) and that its discovery was more or less accidental. Pfizer were testing new drugs for lowering blood pressure, and while sildenafil did not meet the sought after effects in the clinic, many of the test subjects reported an unexpected boner while under the drug. A few brave scientists decided to proceed with these findings, one thing lead to another, and the world saw yet another billion dollar medicine. Stories like this must happen on more or less a daily basis in the underground, don’t you think? For instance, I have heard that many users of 2C-B, a potent and most illegal psychedelic, report a remarkably heightened ability to see in the dark, even long after the primary effects have worn off. Furthermore, users of DIPT, allegedly a mediocre drug in its class, report a profound aural distortion, specifically meaning that music is subjectively perceived as being very out of pitch while under the influence. Finding of this kind could lead to a much better understanding of a number of highly medically relevant areas, far beyond simple recreation. It is a shame we mainstream scientists are no longer tuned in. Can’t you feel the smell of the next blockbuster? If we can take out the psychedelic properties and build on the aforementioned side-effects, I see new medicines against poor night vision and perhaps a completely new mechanism against tinnitus. We used to do these things before. For instance, today’s anti-migraine drugs (the triptanes) are in fact derivatives of LSD. If you ask me, this research approach deserves a revisit, and the abundance of leads is overwhelming if you look just a little outside the box.

So – where to look? Internet is your friend. The underground community is alive and kicking on the web.

Actually, a simple Wikipedia search is not a bad start. You will be surprised to learn how much information is exclusively available there. Then perhaps off to one of the forums such as Bluelight. Their advanced drug discussion section lives up to the name. The vault of Erowid is another classic. Despite not being updated since 2005, Rhodium’s chemistry and pharmacology archives cannot be underestimated. Between 1997 and 2004, The Hive was the foremost forum, but to the best of my knowledge it is no longer available. Some wrongfully believe Alexander Shulgin (at one point the father of two thirds of all US controlled substances) to be part of the underground movement, but he has always been operating in the plain daylight and – he has more papers out in Nature and J. Med. Chem. than you or I will ever have.

I am sure you too have a link or two to share?

To wrap up, I urge all mainstream chemists to take a long, good look at the underground. Do not sink to their level, do not break the law, do not contact them – just read what they write. OK? Even if you hate everything they stand for, you might learn something new. And that is always good.

Great post. Another hang-out for various underground chemists is ScienceMadness.org. These various sites definitely make interesting reading. Particularly interesting is that they often have to explore the synthesis of very simple compounds that we take for granted.

1. Why must every single paper describing a cross-coupling depict the damn mechanism, even though a) organometallic “mechanisms” are not even real mechanisms with curly arrows and b) they are with very few exceptions all the same?

2. C-H activation is always sexy!

3. I have worked with perfluorinated tails before. Love the H-NMRs 🙂 Nothing to see, move along.

4. Did the corresponding author misspell her email? (Missing a “d”?) Ouch in that case.

5. From a quick glace, love it! Must study carefully tomorrow when I have the time. Breaking Bad- followed by bedtime over here. Over and out.